Vagus nerve stimulation (VNS) is an adjunctive treatment for refractory epilepsy in patients who are unsuitable candidates for epilepsy surgery (Ben-Menachem 2002). Worldwide, more than 50 000 epilepsy patients have been treated with VNS. Several studies, including two large double-blind randomized clinical trials (Ben-Menachem et al. 1994;DeGiorgio et al. 2000), have confirmed the efficacy of VNS in different types of epilepsy. Seizure reduction as a result of VNS ranges from 25% to 55%, and varies considerably from patient to patient. In responders, VNS causes either a rapid or a delayed reduction in seizure frequency. However, a significant fraction (approximately one third) of patients do not respond to VNS. Because the mechanism of action of VNS in epilepsy is currently unknown, it is not clear which factors determine the patient's response to the treatment, nor what the most optimal stimulation parameters are.The vagus nerve is a mixed nerve consisting of 20% efferent (motor) and 80% afferent (sensory) fibers. The nucleus of the solitary tract receives the largest number of vagal afferents. The nucleus of the solitary tract in turn Received July 5, 2010; revised manuscript received January 18, 2011; accepted February 8, 2011.Address correspondence and reprint requests to Robrecht Raedt, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. E-mail: robrecht.raedt@ugent.be 1 These authors contributed equally to this work.

Summary: Despite the advent of new pharmacological treatments and the high success rate of many surgical treatments for epilepsy, a substantial number of patients either do not become seizure-free or they experience major adverse events (or both). Neurostimulation-based treatments have gained considerable interest in the last decade. Vagus nerve stimulation (VNS) is an alternative treatment for patients with medically refractory epilepsy, who are unsuitable candidates for conventional epilepsy surgery, or who have had such surgery without optimal outcome. Although responder identification studies are lacking, long-term VNS studies show response rates between 40% and 50% and long-term seizure freedom in 5% to 10% of patients. Surgical complications and perioperative morbidity are low. Research into the mechanism of action of VNS has revealed a crucial role for the thalamus and cortical areas that are important in the epileptogenic process. Acute deep brain stimulation (DBS) in various thalamic nuclei and medial temporal lobe structures has recently been shown to be efficacious in small pilot studies. There is little evidence-based information on rational targets and stimulation parameters. Amygdalohippocampal DBS has yielded a significant decrease of seizure counts and interictal EEG abnormalities during long-term follow-up. Data from pilot studies suggest that chronic DBS for epilepsy may be a feasible, effective, and safe procedure. Further trials with larger patient populations and with controlled, randomized, and closed-loop designs should now be initiated. Further progress in understanding the mechanism of action of DBS for epilepsy is a necessary step to making this therapy more efficacious and established.

This study shows that the characteristics of spontaneous seizures in the intrahippocampal KA model display many similarities to other SE models and human temporal lobe epilepsy.

SUMMARYPurpose: Hippocampal deep brain stimulation (DBS) is an experimental therapy for patients with pharmacoresistant temporal lobe epilepsy (TLE). Despite the successful clinical application of DBS, the optimal stimulation parameters are undetermined. We evaluate the efficacy of a new form of DBS, using continuous stimuli with Poisson distributed intervals (Poisson distributed stimulation, PDS) in the kainate (KA) rat model, a validated model for human TLE. Methods: Status epilepticus was elicited by injection of KA (i.p.). After development of spontaneous seizures, rats were implanted with hippocampal DBS-and depth electroencephalography (EEG) electrodes. After baseline EEG monitoring, one group of rats (n = 13) was treated with PDS and a second (n = 11) received regular high frequency stimulation (HFS) at 130 Hz. Stimulation intensity was 100 lA below the threshold for induction of epileptiform EEG activity.Results: Stimulation intensity was significantly lower for PDS (156 ± 20 lA) than HFS (207 ± 23 lA; p < 0.02). Seven (54%) of 13 rats treated with PDS and 5 (45%) of 11 rats treated with HFS experienced a significant reduction in seizure frequency. In PDS-improved rats, seizure frequency was reduced to 33% (p < 0.01) of baseline value and in HFS-improved rats to 50% (p < 0.01). After termination of PDS, seizure rate returned to baseline value. Discussion: Continuous hippocampal PDS significantly reduces the number of spontaneous seizures. Compared to regular HFS, there is a slightly larger number of improved rats and a larger efficacy at a considerably lower stimulus intensity. The first two observations leave room for optimization, whereas a lower intensity is beneficial for battery life.

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